Abstract 1814: A long-acting and CD122-enhanced IL-2 analog, HM16390, shows a potent and durable anti-tumor effect in both syngeneic B16F10 or CT26 mouse models
Authors: Jinyoung Kim, Jaehyuk Choi, Yu Yon Kim, Seongju Jeong, Sang Hyun Park, Sungmin Bae, Daejin Kim, In Young Choi
Journal: Cancer Research (2023)

Abstract Although recombinant IL-2 (aldesleukin) was approved for the treatment of metastatic renal cell carcinoma and melanoma, its suboptimal ligand binding affinity required high-dose administrations, resulting in dose-limiting toxicity such as vascular leak syndrome. To overcome the limitation of the current IL-2 therapy, a number of pharmaceutical companies have developed CD25 binding attenuated IL-2 muteins via various platform technology. These physical changes, however, accompanied a decrease in CD122-mediated signaling which was associated with cytotoxic lymphocytes expansion, leading to unsatisfied clinical consequences. In this context, we developed HM16390, a long-acting IL-2 analog with enhanced CD122 binding affinity to elicit potent anti-tumor efficacy. Furthermore, optimal binding affinity to CD25 was incorporated to prevent from unwanted toxicity. The pharmacokinetics in mice after single subcutaneous administration of HM16390 supported an extended duration of action (t1/2= 24.5 hr, bioavailability= 43.0%). To further investigate anti-tumor effect on various immunological conditions, syngeneic tumor mouse models, which are representing highly immunogenic colon cancer (CT26) and poorly immunogenic melanoma (B1F10), were chosen. After two weeks treatment in CT26 mice, complete response (CR) was observed in 89% and 100% of the mice by once weekly treatment of HM16390 at 2.1 and 8.5 mg/kg respectively, while only 22% of the mice showed CR by 5 consecutive day treatment per week of aldesleukin at 3.0 mg/kg. The cured mice had no evidence of relapse after tumor re-challenges at days 50 and 152. This immunological memory response against the CT26 tumor was demonstrated by significant increase in tumor-specific memory T cells in lymphoid organ and blood. Next, after four weeks treatment in B16F10 mice, once weekly treatment of HM16390 was well tolerated up to 42 mg/kg, and led to significant and dose-dependent retardation in tumor growth (vs syngeneic tumor vehicle) from 62.9% to 96.4% as well as dose-dependently prolonged median overall survival from 15 to 38 days (14 days in syngeneic tumor vehicle) at the dose range of 0.34 to 42 mg/kg. Of note, at doses ≥17 mg/kg, CR was observed in up to 22% of the mice. To sum up with the results, HM16390 has a dose-dependent and potent anti-tumor efficacy in murine models with the broad range of the immunogenic condition via CD122-enhanced IL-2 agonism. Citation Format: Jinyoung Kim, Jaehyuk Choi, Yu Yon Kim, Seongju Jeong, Sang Hyun Park, Sungmin Bae, Daejin Kim, In Young Choi. A long-acting and CD122-enhanced IL-2 analog, HM16390, shows a potent and durable anti-tumor effect in both syngeneic B16F10 or CT26 mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1814.